Nephrogenic Systemic Fibrosis

NORD gratefully acknowledges Shawn E. Cowper, MD, Associate Professor of Dermatology and Pathology, Yale University and Ali K. Abu-Alfa, MD, FASN, Professor of Medicine, Head, Division of Nephrology and Hypertension, American University of Beirut for assistance in the preparation of this report

Synonyms of Nephrogenic Systemic Fibrosis

gadolinium-associated nephrogenic systemic fibrosis

nephrogenic fibrosing dermopathy

NSF

General Discussion

Nephrogenic systemic fibrosis (NSF) is a rare disorder that occurs in some individuals with reduced kidney function, who have been exposed to an intravenous contrast material that contains gadolinium. A contrast material is a dye that is sometimes used during magnetic resonance imaging (MRI). The term, fibrosis, refers to the thickening and scarring of connective tissue, most often the consequence of inflammation or injury. NSF is characterized by thickening and hardening (fibrosis) of the skin, subcutaneous tissues, and, sometimes, underlying skeletal muscle. The arms and legs are most often affected. In some cases, the skin on the trunk can also become involved. This proliferation of fibrotic tissue may become systemic, extending to other areas including the smooth, delicate membrane that surrounds the lungs (pleura), the sac surrounding the heart (pericardium), the thin sheet of muscle that aids respiration by moving up and down when breathing (diaphragm), and the outermost layer (dura mater) of the three membranes covering the brain and spinal cord.

NSF was thought to predominantly involve the skin and was originally referred to as nephrogenic fibrosing dermopathy. However, it is now known that it may involve several internal organs (systemic disorder), potentially leading to a progressive and severe disease course. NSF has not been reported in individuals with normal kidney function.

Since September of 2010, the U.S. Food and Drug Administration (FDA) has required that gadolinium-based contrast agents (GBCA) carry a warning on their labels about the risk of NSF when administered in certain individuals with kidney disease. In addition, the FDA also stated that three specific gadolinium-based contrast agents (Magnevist ®, OmniscanTM, and Optimark ®) were contraindicated in individuals with severe chronic kidney disease or acute kidney injury. These three agents were the ones most often associated with NSF.

Signs & Symptoms

The symptoms of NSF may develop slowly over a few weeks to a few months after exposure to gadolinium-based contrast agents. The severity and progression of the disorder can vary from one person to another. The disorder can have a rapid, progressive course and can cause debilitating symptoms. In rare, rapidly-progressive cases, NSF can contribute to the development of severe, life-threatening complications.

The initial symptoms of NSF usually involve the skin, with a gradual tightening or thickening effect. Affected individuals may experience reddened (erythematous) or darkened patches or papules especially on the extremities. The areas between the ankles and the thighs and the wrists and the upper arms are most commonly affected. Swelling (edema) may also occur and the skin may be itchy (pruritic). In some cases, the skin may appear shiny. Skin abnormalities are usually symmetric, which means that the size, shape and location of the lesions are similar on both sides of the body.

Over time, affected areas may eventually resemble the texture of an orange peel (peau d’orange). Skin hardening (induration) can become severe, causing chronic pain and loss of flexibility. The affected areas of skin can become hard to the touch. In general, the facial skin is not involved. In addition to the skin, underlying tissue may also be affected including the layer of connective tissue beneath the skin (subcutis), the tough band of fibrous tissue beneath the subcutis (fascia) and skeletal muscle.

In some cases, skin tightening and hardening may affect the range of motion and flexibility of the joints, causing contractures. A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint. Severely affected individuals can lose the ability to walk or to fully extend the upper and lower limbs, potentially becoming wheelchair bound.

Complaints of muscle weakness are also common in individuals with NSF. Flesh-colored, reddish, or brownish papules (small, solid bumps arising from the skin) have been reported, and yellow scleral plaques (yellow areas in the whites [sclera] of the eyes) have also been observed.

Additional symptoms associated with NSF are highly variable depending upon the specific organ systems involved. NSF can potentially affect multiple organ systems and structures of the body including the lungs, hearts, esophagus and diaphragm. Involvement of the lungs or diaphragm can lead to a variety of breathing (respiratory) complications. Involvement of the heart can impair the ability of the heart to pump blood throughout the body.

Causes

The exact underlying cause of NSF is not fully understood. The disorder occurs in individuals with advanced kidney disease who have been exposed to gadolinium-based contrasts agents that are used in magnetic resonance imaging.

Gadolinium is a heavy metal with paramagnetic qualities that cause it to respond differently within a magnetic field. Because of this trait, gadolinium has been used for magnetic resonance imaging examinations. Gadolinium is considered toxic and, in order to be used in contrast dyes, is bound to other molecules to facilitate its passage through the body. Gadolinium contrast agents are ultimately excreted through the kidneys. Individuals with impaired kidney function cannot adequately and quickly eliminate GBCA from the body. Researchers believe this prolonged excretion may lead to a breakdown of the contrast chemical, with release of the Gadolinium atom (dechelation). This foreign material may then lead to a process resembling a chronic wound healing reaction, with abundant production of collagen.

In addition to kidney disease and exposure to GBCAs, individuals with NSF may have a “proinflammatory” state, which refers to any condition that causes an inflammatory reaction in the body. In individuals who had developed NSF, this has included recent major surgery, infection, malignancy or the formation of blood clots (thrombosis). Many individuals with NSF have had recent vascular surgery or a thrombotic condition before the onset of the disorder. The exact relationship between these inflammatory conditions and risk for development of NSF is not known.

Researchers have also detected the presence of “circulating fibrocytes” (CFs) in the skin of individuals with NSF. CFs are circulating cells that respond to tissue damage by exiting the circulation and maturing into cells that produce fibrous tissue (collagen). They are normally participants in the wound healing process. Researchers believe that these cells are inappropriately summoned to the skin in great numbers, despite the lack of an obvious injury. Currently investigators suspect the dechelation event allows the CFs to home to the skin, where they produce the abundant collagen typical of NSF. The precise details of this process are not fully understood and require further study.

Affected Populations

NSF was first reported in the medical literature in 2000. The first case was noted in 1997. Researchers believe that the perceived safety and increased availability of gadolinium-based contrast dyes contributed to the rise of NSF since 1997.

NSF affects men and women in equal numbers. The exact incidence or prevalence of the disorder is not known, although cases have been identified all over the world, typically in developed countries. More than 375 cases have been identified by the NSF Registry. The disorder can affect children, adults or the elderly. It is most common in the middle-aged and no known ethnic or racial predilection exists. Confirmed cases of NSF have only occurred in individuals with kidney disease who have been exposed to gadolinium-based contrast agents.

Researchers believe that the increased awareness of the disorder and subsequent precaution or avoidance of using gadolinium-based contrast agents in individuals with decreased kidney function will lead to a decrease in the number of cases of NSF. Since identification of gadolinium as a potential trigger, European and American medical agencies have banned the use of certain GBCAs in individuals with renal disease. According to the International NSF Registry, there have been very few new cases of NSF since this ban went into effect.

Related Disorders

Symptoms of the following disorders can be similar to those of NSF.

Scleroderma is a rare connective tissue disorder characterized by abnormally increased production and accumulation of collagen, the body’s major structural protein, in skin and other organs of the body. There are systemic and localized forms of scleroderma. Systemic scleroderma is characterized by hardening (induration) and thickening of the skin and abnormal degenerative changes and formation of fibrous tissue (fibrosis) in certain organs of the body including the lungs, heart, kidneys, and GI tract. Associated symptoms, which may vary widely from case to case, may include abnormal discoloration of and pain affecting the fingers and toes upon exposure to cold temperatures (Raynaud’s phenomenon); abnormal tightness, thickening, “waxiness,” and loss of elasticity of the skin; shortness of breath; difficulty swallowing; muscle weakness; joint pain; heart abnormalities including irregular heart beats (palpitations); kidney (renal) abnormalities; and/or other symptoms and findings. In individuals with localized scleroderma, involvement is restricted to the skin, tissue under the skin (subcutaneous tissue), and, in some cases, underlying muscle and bone. Linear scleroderma is a localized form of scleroderma that may involve only certain areas of the body, such as an arm, a leg, or a portion of the face. It is characterized by multiple lesions of the skin, abnormally increased or decreased skin pigmentation (hyper- or hypopigmentation), and associated atrophy of the skin, subcutaneous tissue, muscle, and bone. Although the exact cause of scleroderma is unknown, researchers suggest that the disorder represents an abnormal autoimmune response. (For further information, choose “scleroderma” as your search term in the Rare Disease Database.)

Scleromyxedema is a rare skin disorder characterized by widespread reddish papules and abnormally thickened and hardened skin. The range of motion of affected areas such as the face, fingers and arms and legs is often decreased. In scleromyxedema, the pharynx and the upper airways may become involved causing serious breathing (respiratory) complications. Other organ systems including the lungs and the heart may also be affected. Joint pain affecting multiple joints (polyarthritis) may also occur. The disorder primarily affects middle-aged adults. The cause of scleromyxedema is unknown.

Eosinophilic fasciitis is a rare disorder characterized by inflammation of the tough band of fibrous tissue beneath the skin (fascia). The arms and legs are most often affected. Inflammation is caused by the abnormal accumulation of certain white blood cells including eosinophils in the fascia. Eosinophilic fasciitis eventually causes the skin to swell and slowly thicken and harden (induration). The disorder most commonly affects middle-aged adults. The exact cause of eosinophilic fasciitis is unknown. Some researchers believe that eosinophilic fasciitis is a variant of scleroderma (systemic sclerosis), an autoimmune connective tissue disorder characterized by hardening of the skin. (For more information on this disorder, choose “eosinophilic fasciitis” as your search term in the Rare Disease Database.)

Diagnosis

Diagnostic criteria for NSF have been recently developed. A diagnosis of NSF is usually made based upon a detailed patient history, a thorough clinical examination and identification of characteristic findings. Surgical removal and microscopic study of a small sample of affected skin tissue (skin biopsy) is required to verify the diagnosis. Additional tests may be performed to exclude several other disorders that can resemble NSF.

Standard Therapies

Treatment

There is no specific, consistently effective therapy available for individuals with NSF. Improvement in kidney function, either spontaneously after acute kidney injury or post-transplantation, appears to slow, or stop the progression of NSF. In some cases with improvement in kidney function, a gradual reversal of the disease process may occur over time.

A wide variety of different therapies have been tried in individuals with NSF with varying results. These therapies are detailed in the investigational therapies section below.

Because NSF can damage and restrict the joints, early physical therapy and medications for pain control may have a role in the treatment of affected individuals.

Individuals maintained on chronic hemodialysis and peritoneal dialysis have a significantly higher risk of developing NSF compared with individuals with advanced chronic kidney disease who have not yet started dialysis. Patients with acute kidney injury who have not been dialyzed within the 2 days preceding a GBCA injection may have a very high risk for NSF. Whether hemodialysis has value in preventing NSF post-exposure is unknown. Immediate hemodialysis within 2 hours of GBCA injection in patients on hemodialysis, peritoneal dialysis or those with severe acute kidney injury is recommended based on theoretical and observational data.

Investigational Therapies

Investigational therapies are treatment modalities that are not considered standard therapies for a particular disorder and have not been approved for the treatment of that disorder. Many times the benefits of these therapies have been noted anecdotally in only a few patients. In addition, in individuals with NSF, the follow-up time and techniques required to assess a therapy’s effectiveness have not been determined.

A variety of different medications have been used to treat individuals with NSF including thalidomide, cytoxan, pentoxifylline, intravenous immunoglobulin, imatinib Mesylate, Alefacept, and oral steroids such as prednisone.

Two procedures that have been used to treat individuals with NSF include extracorporeal (outside the body) photopheresis and plasmapheresis. During photopheresis, the blood of an affected individual is withdrawn and treated with a drug that sensitizes the blood to ultraviolet light. The blood is then exposed to ultraviolet light and ultimately returned to the body.

Plasmapheresis is a procedure for removing unwanted substances (toxins, metabolic substances and plasma components) from the blood. Blood is removed from the patient and the solid blood cells are separated from the liquid plasma. The patient’s plasma is then replaced with donor human plasma or albumin, which is retransfused, along with the patient’s original blood cells. This therapy is still under investigation to analyze side effects and effectiveness.

Some individuals with NSF who have undergone a kidney transplant have exhibited a significant improvement in the symptoms of NSF, although this response is not universal. Consequently, some researchers have advocated a kidney transplant for affected individuals who are eligible. In general, the earlier this transplant can be accomplished the better, as excess collagen production is ongoing and difficult to reverse once established. Many of these patients are already on kidney transplant waiting lists. NSF should not be used as an excuse to exclude a patient from receiving a transplanted kidney.

The above mentioned therapies require further research and in-depth clinical studies to determine their long-term safety and effectiveness as treatments for individuals with NSF.

Prevention of NSF is the key to eradicating this disease. The FDA currently requires screening for kidney function in individuals at risk for having kidney disease before the administration of a GBCA. In addition, using alternative imaging modalities that do not utilize GBCAs should be used whenever possible in the renal population. If after assessment of risks and benefits a GBCA administration is unavoidable in this setting, the use of low-risk GBCAs has been advocated.

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